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WO2012011128A1 - Préparation de dérivés de prostaglandines - Google Patents

Préparation de dérivés de prostaglandines Download PDF

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Publication number
WO2012011128A1
WO2012011128A1 PCT/IN2011/000484 IN2011000484W WO2012011128A1 WO 2012011128 A1 WO2012011128 A1 WO 2012011128A1 IN 2011000484 W IN2011000484 W IN 2011000484W WO 2012011128 A1 WO2012011128 A1 WO 2012011128A1
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Prior art keywords
formula
compound
bimatoprost
mixture
vaa
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Ceased
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PCT/IN2011/000484
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English (en)
Inventor
Venkata Lakshmi Narasimha Rao Dammalapati
Praveen Kommana
Lakshmi Narayana Chennuru
Srinivasu Gunnam
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Aptuit Laurus Pvt Ltd
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Aptuit Laurus Pvt Ltd
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Publication of WO2012011128A1 publication Critical patent/WO2012011128A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention generally relates to a method for derivatization of intermediate of prostaglandins, a process for its conversion in to prostaglandins and prostaglandin analogs, namely bimatoprost, a purification process using preparative chiral chromatography and pharmaceutical compositions containing the same.
  • Prostaglandins are a family of biologically active compounds that are found in virtually all tissues and organs. These naturally occurring prostaglandins have extremely complex biological functions (e.g. stimulation of smooth muscles, dilation of smaller arteries and bronchi, lowering blood pressure, etc.). Synthetic prostaglandins are for example clinically used to treatment of glaucoma and elevated ocular hypertension (IOP).
  • IOP elevated ocular hypertension
  • the marketed PG analogs used to reduce IOP include Latanoprost, ((9S, 11R, 15R)-9, 11, 15-trihydroxy-17-phenyl-18, 19, 20-trinor-5Z-prostenoic acid, isopropyl ester), is available in the market under the brand name Xalatan® in the form of 0.005% ophthalmic solution.
  • Bimatoprost ((9S, 11R, 15S)-9, 11, 15-trihydroxy-17-phenyl-18, 19, 20-trinor-5Z, 13E- prostadienoic acid, ethyl amide), is available in the market under the brand name Lumigan® in the form .
  • Pi is p-phenyl benzoyl or benzoyl, "— "represents an optional double bond, R 3 is alkoxy or alkyl amino
  • the scheme 1 method is difficulty to operate in commercial scale since the required stereochemistry is obtained by column chromatography method.
  • the chromatographic separation of diastereomers is unfavorable process for scale up due to its multi step nature and cost.
  • the difficulty in chromatographic separation stems from the fact that the two epimers do not differ greatly in their affinity for the adsorbent, and thus their retention times are too close to allow efficient separation in one chromatographic step.
  • U.S. Patent No. 7,157,590 (“the '590 patent”) disclosed a process for preparing prostaglandins by stereo selective reduction of carbonyl function of the PPB (p-phenyl benzoyl) protected compound with (-)-B-chlorodiisopinocamphenyl borane (DIP-Cl) to yield a diastereomeric mixture of corresponding 3-hydroxyl compound.
  • PPB p-phenyl benzoyl
  • DIP-Cl diastereomeric mixture of corresponding 3-hydroxyl compound.
  • the '590 patent further discloses a method of recycling of resulting mother, liquor to the starting material by oxidizing the hydroxyl group.
  • the process disclosed in the '590 patent is schematically represented by the scheme 2.
  • the present invention provides a process for the preparation of prostaglandins and prostaglandin analogs by derivatization of 3-hydroxy analogs with simple protecting groups such as p-nitrobenzoyl and benzoyl groups, avoids expensive column chromatography to increase the desired isomer ratio.
  • the process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.
  • the present invention provides a process for the preparation of compound of Formula I
  • R 3 is selected from alkoxy or alkyl amino and "— " represents an optional double bond; the process comprising:
  • 'Pi' represents a benzoyl (Bz) or a p-nitrobenzoyl group (PNB); to yield a mixture of compounds of Formula Va and Vb
  • the present invention provides a process for isolating the compound of Formula Vaa by solvent crystallization; comprising:
  • organic solvent SI is selected from the group consisting of C 1-4 alcohols, esters, ethers, hydrocarbons, nitriles, ketones, water and their mixtures.
  • the present invention provides a compound of the Formula Vaa.
  • the present invention provides a compound of Formula Vaa
  • the present invention provides a process for the preparation of compound of Formula I, comprising:
  • R 3 is selected from alkoxy or alkyl amino and "— " represents an optional double bond; the process comprising:
  • --" represents an optional double bond
  • R 3 is selected from alkoxy or alkyl amino and "-- represents an optional double bond
  • the present invention provides a process purification of compound of Formula I
  • R 3 is selected from alkoxy or alkyl amino and "— " represents an optional double bond, comprising; subjecting the compound, of Formula I to a preparative chiral HPLC with a suitable eluent selected from C 1-4 alcohol, water or a mixture thereof, to obtain the pure compound of Formula I.
  • the present invention provides a method for preparing the pharmaceutical composition for treating ocular hypertension by combining therapeutically effective amount of compound of Formula I prepared according to the present invention with ophthalmically acceptable vehicle.
  • the present invention provides, a process for the preparation of compound of Formula I
  • R 3 is selected from alkoxy or alkyl amino and "— " represents an optional double bond; the process comprising:
  • 'Pi' represents a benzoyl or a p-nitrobenzoyl group; to yield a mixture of compounds of Formula Va and Vb; (Vb) derivatizing t a mixture of compounds o
  • the starting material compound of Formula VI is known in the art and can be prepared by any known method, for example, a compound of Formula VI can be synthesized by the process mentioned in US 5698733, the content of which is incorporated herein by reference.
  • the step of stereo selective reduction of the carbonyl group of the compound of Formula VI, wherein 'Pi' represents a benzoyl or a p-nitrobenzoyl group, preferably benzoyl group, is carried out with (-)-B-chlorodiisopinocamphenylborane or with borane in the presence of 2-alkyl-CBS-oxazaborolydines at temperature suitable for keto reduction. More preferably the reduction is carried out with (-)-B- chlorodiisopinocamphenylborane in an organic solvent at a temperature of about -50°C to about +10°C, preferably at about -35°C to about -25°C.
  • the organic solvent is selected from tetrahydrofuran (THF), ether, 1, 2 -dimethoxy ethane, toluene, hexane, dichloromethane or mixtures of these solvents; more preferably the organic solvent is THF.
  • THF tetrahydrofuran
  • ether 1, 2 -dimethoxy ethane, toluene, hexane, dichloromethane or mixtures of these solvents
  • THF tetrahydrofuran
  • unwanted process impurities such as pinines formed during the stereo selective reduction of the carbonyl group of the compound of Formula VI, can be removed by a column chromatography method known in the art and unwanted R-isomer can be separated by a derivatization process of the present invention that involves use of benzoyl or p-nitrobenzoyl groups.
  • the organic solvent includes, but is not limited to C 1-4 alcohols such as methanol, ethanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; ethers such as diethyl ether, THF, methyl tertiary butyl ether, diisopropyl ether and the like, hydrocarbons such as hexane, heptane, cyclohexane, toluene and the like; water and their mixtures.
  • C 1-4 alcohols such as methanol, ethanol, isopropanol and the like
  • esters such as ethyl acetate, isopropyl acetate and the like
  • ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, THF, methyl tertiary butyl ether, hexane, toluene and mixtures thereof; more preferably ethyl acetate.
  • the catalyst used, such as dimethyl amino pyridine (DM AP) and the like and the base include organic bases such as triethyl amine, . diisopropylamine, diisopropyl ethylamine and the like and mixtures thereof; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like and mixtures thereof; preferably the base is triethyl amine.
  • the reaction temperature should be sufficient to effect the reaction.
  • the reaction temperature may be from about ambient temperature to about reflux temperature.
  • the reaction temperature is at about 20°C to about 65°C, more preferably at about 25°C to about 35°C.
  • the present invention provides a process for isolating the compound of Formula Vaa, wherein Pi represents a benzoyl group, P 2 represents a p-nitrobenzoyl group, obtained by a process comprising crystallizing the mixture of compounds of Formula Vaa and Vbb, where the resultant compound of Formula Vaa may have a chiral purity of 99.9: 0.1 % of S : R ratio as determined by chiral HPLC.
  • the present invention further provides a process for isolating the compound of Formula Vaa, wherein Pi represents a benzoyl group, P 2 represents a p-nitrobenzoyl group, comprising:
  • the organic solvent SI include, but are not limited to C 1-4 alcohols such as methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, tertiary butanol and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n- propyl acetate, isobutyl acetate, n-butyl acetate, and the like; ethers such as THF, 1,4- dioxane, diethyl ether, diisopropyl ether, methyl isobutyl ether, methyl tertiary butyl ether (MTBE) and the like; hydrocarbons selected from the group consisting of aromatic hydrocarbons such as benzene, toluene,
  • the organic solvent SI is selected from the group consisting of methanol, isopropanol, ethyl acetate, methyl tertiary butyl ether, hexane, heptane, acetonitrile, acetone, water and their mixtures; more preferably a mixture of ethyl acetate and n-hexane.
  • the resultant reaction mass may be heated.
  • the solution is heated at a temperature of at least about 30°C to about reflux temperature.
  • the solution is heated at about 40°C to about 80°C; more preferably at temperature about 50°C to about 60°C.
  • the resultant reaction mass at a temperature from about 30°C or less; such that the resulting compound of formula Vaa can be isolated by conventional techniques, for example filtration.
  • the temperature during stirring can range from about -10°C to about + 40°C, preferably at about 25°C to about 35°C.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 70°C, preferably at about 25°C to about 35°C.
  • the above crystallization process may be repeated one or more times to get a chiral purity typically equal to or greater than about 99.9% of S-isomer by weight as determined using chiral HPLC.
  • the compound of formula Vaa recovered using the process of the present invention, having chiral purity equal to or greater than about 99.9% of S-isomer by weight as determined using chiral HPLC.
  • the present invention provides a compound of formula Vaa
  • the present invention provides a process for the preparation of a compound of Formula I
  • R 3 is selected from alkoxy or alkyl amino and "— " represents an optional double bond, obtained by a process comprising providing a compound of Formula Vaa, as a starting material, where the resultant compound of Formula I may have a purity of greater than about 99.5% as determined by chiral HPLC.
  • the present invention further provides a process for a preparation of a compound of Formula I, comprising:
  • R 3 is selected from alkoxy or alkyl amino and "— " represents an optional double bond.
  • the step a) of the foregoing process of deprotection of the compound of formula Vaa may include with a base in an organic solvent.
  • the base include, but are not limited to organic bases such as triethyl amine, diisopropyl amine, diethyl amine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.
  • the base is potassium carbonate.
  • the organic solvent include, but are not limited to C 1-4 alcohols such as methanol, ethanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; chlorinated solvents such as methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like; and mixtures thereof.
  • the organic solvent is selected form the group consisting of methanol, ethyl acetate, methylene chloride, n-hexane; more preferably methanol, methylene chloride and mixtures thereof.
  • the step b) of the foregoing process may include reduction in presence of DIBAL-H in an organic solvent at a temperature of about -80°C to about -10°C.
  • the organic solvent include, but are not limited to toluene, THF, diethyl ether, methyl tertiary butyl ether, methylene chloride, ethyl acetate, isobutyl acetate and the like and mixtures thereof.
  • the organic solvent is methylene chloride, THF and mixtures thereof; and the temperature is about -80°C to -75°C.
  • the resultant triol compound may be crystallized from a suitable organic solvent at a temperature of about 20°C to about 45°C.
  • the suitable organic solvent include, but is not limited to ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; C 1-4 alcohols such as methanol, ethanol, isopropanol, n- propanol, isobutanol, n-butanol, tertiary butanol and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, and the like; and mixtures thereof.
  • the suitable organic solvent is selected from acetone, ethyl acetate, n-hexane and mixtures thereof, more preferably mixture of acetone and ethyl acetate.
  • the step c) of the foregoing process may include reacting the resultant triol compound with 5-(triphenylphosphoranylidene) pentanoic acid bromide in presence of alkali metal tertiary butoxide in an organic solvent at a temperature of about -20°C to about 0°C, to obtain acid compound of Formula II.
  • the alkali metal tertiary butoxide include, but are not limited to potassium tertiary butoxide, magnesium tertiary butoxide, lithium tertiary butoxide and the like, preferably the alkali metal tertiary butoxide is potassium tertiary butoxide.
  • the organic solvent include, but is not limited to toluene, THF, diethyl ether, methyl tertiary butyl ether, methylene chloride, and the like and mixtures thereof.
  • the organic solvent is THF and the temperature is about 5°C to about 10°C.
  • the present invention further provides a process for the preparation of a compound of Formula I (wherein R 3 is alkoxy, preferably methoxy or isopropoxy and "— " represents an optional double bond) includes esterifying an acid compound of Formula II.
  • the esterification of the acid compound of Formula II can be carried out in the presence of an alkyl iodide and a base in an organic solvent.
  • a useful alkyl iodide includes, but is not limited to methyl iodide or isopropyl iodide.
  • the base includes, but is not limited to sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, diazabicyclo [5.4.0] undec-7-ene; preferably the base is sodium carbonate.
  • the organic solvent includes, but is not limited to methanol, ethanol, acetone, ethyl acetate, toluene, THF, diethyl ether, methyl tertiary butyl ether, methylene chloride, dimethyl formamide, and the like and mixtures thereof; preferably the organic solvent is dimethyl formamide.
  • the present invention further provides a process for the preparation of bimatoprost (a compound of Formula I, wherein R 3 is alkyl amino, preferably ethylamino and "— " represents a double bond) includes amidation of a compound of Formula I (wherein R 3 is alkoxy, preferably methoxy and "— " represents a double bond).
  • the amidation of the compound of Formula I (wherein R 3 is alkoxy, preferably methoxy and "— " represents a double bond) can be carried out ,with ethyl amine at temperature about 20°C to about 50°C, preferably at about 25°C to about 35°C to obtain crude bimatoprost, where the ethyl amine may be in the form of an aqueous or anhydrous form, for example aqueous ethyl amine can be used, preferably 70% aqueous ethyl amine can used.
  • the crude bimatoprost as obtained by -a process of the present invention may contain about 3% of 15 (S)-5,6-trans bimatoprost of Formula A.
  • the quality of the crude bimatoprost can be improved by purifying the bimatoprost using preparative chiral column chromatography method or solvent purification method to selectively reducing the content of undesired 15 (S)-5,6-trans bimatoprost of Formula A.
  • the present invention provides, crude bimatoprost thus obtained may be purified by preparative chiral column chromatography method such as normal phase or reverse phase chromatography; or solvent purification method.
  • the normal phase preparative chiral column chromatography method can be performed using preparative chiral column and an eluent comprising an alcohol.
  • the eluent alcohol is selected from methanol, ethanol, or isopropanol and the like.
  • the eluent is methanol.
  • the normal phase preparative chiral chromatography column may be selected by any chiral columns known in the art, for example from 250 ⁇ 30 mm to 500 x 50 mm, preferably 500 ⁇ 50 mm of CHIRALPAK AD-H with about 5 ⁇ particles, manufactured by Daicel, Japan.
  • Flow rate of the mobile phase may be selected from about 10 ml to 80 ml per minute, preferably about 30 ml to 60 ml per minute, more preferably about 50 ml per minute.
  • Conditions for the normal phase preparative chiral column chromatography are known to the person skilled in the art.
  • the organic solvent includes, but is not limited to ethers such as diethyl ether, isopropyl ether, methyl isobutyl ether, methyl tertiary butyl ether, THF, 1,4-dioxane and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, and the like, and mixture thereof; preferably the organic solvent is methyl tertiary butyl ether.
  • ethers such as diethyl ether, isopropyl ether, methyl isobutyl ether, methyl tertiary butyl ether, THF, 1,4-dioxane and the like
  • hydrocarbons such as n-hexane, n-heptane, cyclohexane, and the like, and mixture thereof
  • the organic solvent is methyl tertiary butyl ether.
  • the reverse phase preparative chiral column chromatography method can be performed using reverse phase column chromatography and an eluent comprising an alcohol and water.
  • the eluent used comprises an alcohol, such as methanol, ethanol, or isopropanol and the like.
  • the alcohol and water are used in a ratio of about 1 :30 to about 30:1, preferably about 5:20 to about 20:5 or in a gradient mode.
  • the reverse phase preparative chiral chromatography column may be selected by any chiral columns known in the art, for example, preferably 250 x 50 mm Inertsil Prep ODS with 10 ⁇ particles.
  • the mobile phase additive is added at a level of 0.01%, 0.05%, 0.10%, 0.25% or 0.5%. Conditions for the reverse phase preparative chromatography are known to the person skilled in the art.
  • the solvent purification method can be performed by dissolving the crude bimatoprost obtained by the process of the present invention in an organic solvent
  • the organic solvent include, but are not limited to C alcohols such as methanol, ethanol, isopropanol, butanol and the like and mixtures thereof; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, and the like and mixtures thereof; ethers such as THF, 1,4-dioxane, diethyl ether, diisopropyl ether, methyl isobutyl ether, MTBE and the like and mixtures thereof.
  • the solvent selected from the group consisting of methanol, isopropanol, ethyl acetate, and MTBE; more preferably ethyl acetate.
  • the solvent may be heated to obtain a solution at a temperature of from about ambient temperature to about reflux temperature, preferably at about 25° to about 80°C, more preferably at about 45°C to 65°C. Then, optionally, adding an antisolvent to the resultant solution, wherein the antisolvent include, but are not limited to hydrocarbons such as hexane, heptane, toluene and the like and mixture thereof, preferably hexane.
  • the reaction solution may be cooled at a temperature from about 30°C or less such that the bimatoprost can be isolated by conventional techniques.
  • the present invention provides a bimatoprost, obtained by the process described herein, having a chiral purity of at least about 98% as measured by chiral HPLC, preferably at least about 99% as measured by chiral HPLC; more preferably at least about 99.5% as measured by chiral HPLC; a 15 (S) - 5,6-trans bimatoprost of Formula A of less than about 0.4% as measured by HPLC, preferably less than about 0.2 % as measured by HPLC, more preferably less than about 0.15% as measured by HPLC; and substantially free of one or more of impurities as described in Table 1.
  • Form J wherein the word “substantially free” refers to bimatoprost having individual or total of less than about 0.1% of Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, Formula I, or Formula J, as measured by HPLC, more preferably individual or total of less than about 0.05% Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, Formula I, or Formula J, as measured by HPLC.
  • alkoxy refers to a methoxy, ethoxy, propoxy and isopropoxy group.
  • alkylamino refers to a methyl amino, ethyl amino, propylamine isopropylamino group.
  • not detected refers to bimatoprost having less than 0.01% by HPLC of one or more of impurities.
  • the present invention provides a bimatoprost, obtained by the above process, as analyzed using chiral high performance liquid chromatography ("chiral HPLC”) with the conditions described below:
  • the present invention provides a bimatoprost, obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions described below:
  • the present invention also encompasses a pharmaceutical composition comprising bimatoprost, obtained by a process of the present invention in the manufacture of a medicament for topical ocular use.
  • the composition is prepared by combining a therapeutically effective amount of bimatoprost of the present invention, as an active ingredient, with conventional pharmaceutically-acceptable excipients, e.g. an ophthalmically- acceptable vehicle.
  • the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v.), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
  • compositions of the present invention may further comprise various formulatory ingredients, such as ophthalmically acceptable diluents, buffers, hydrochloric acid, sodium hydroxide, antimicrobial preservatives, stabilizers, tonicity adjustors, viscosity-enhancing agents, chelating agents, antioxidants, surfactants and/or solubilizers and combinations thereof.
  • diluent is purified water.
  • Preservatives are used in multi-use ophthalmic formulations to prevent microbial contamination of the composition after the packaging has been opened.
  • a number of preservatives have been used including quaternary ammonium salts, mercury compounds, alcohols and stabilized chlorine dioxide.
  • Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, phenylmercuric nitrate, Polyquad(TM).
  • Viscosity-enhancing agents may be added as needed or convenient. They include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, polyethylene glycol, or combinations thereof.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, dextrose, propylene glycol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Hydrochloric acid or sodium hydroxide may be used to adjust the pH of these formulations as needed.
  • Preferred surfactants are, for example, polyethoxylated castor oil, Tween 80, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose cyclodextrin.
  • excipient components which may be included in the ophthalmic preparations, are chelating agents.
  • the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
  • Example 1 Preparation of (3aR, 4R, 5R, 6aS)-4-[3S-hydroxy-5-phenyl-lE-pentenyl]-5- (benzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one.
  • Example 2 Preparation of (3aR, 4R, 5R, 6aS)-4-[3-S-(p-nitrobenzoyloxy)-5-phenyl-lE- pentenyl]-5-(benzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one.
  • Example 2 residue 150 gms
  • ethyl acetate 600 ml
  • n- hexane 900 ml
  • Example 2 residue 150 gms
  • ethyl acetate 600 ml
  • n- hexane 900 ml
  • Example 2 residue 150 gms
  • ethyl acetate 600 ml
  • n- hexane 900 ml
  • the wet product was dried at 45 °C to 50°C under reduced pressure to provide the title compound Yield: 100 gms.
  • Ratio of elutes 40% ethyl acetate in hexanes, 60%» ethyl acetate in hexanes, followed by 100% ethyl acetate.
  • Example 5 Preparation of (3aR, 4R, 5R, 6aS)-4-[3S-hydroxy-5-phenyl-lE-pentenyl]-5- (hydroxy)-hexahydro-2H-cyclopenta[b]furan-2-ol.
  • Example 5 Into a 3 liter 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged THF (275 ml), 4-carboxybutyl triphenylphosphonium bromide (90gm) at temperature 25° to 30°C. Cooled the reaction mass to -8°C to -12°C and added potassium tert-butoxide solution (400 ml) (1 molar solution in THF). Charged Example 5 product (15 gm in 75 ml THF) at 5°C to 10°C and maintained the reaction mass for 2 hours at same temperature.
  • the organic layer was removed by distillation from the reaction mass under vacuum at temperature 35°C to 45°C to yield title compound as residue.
  • Example 8 Purification of Bimatoprost using reverse phase preparative chiral chromatography.
  • Example 9 Purification of Bimatoprost using solvent-antisolvent method.

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Abstract

L'invention concerne un procédé de préparation de dérivés de prostaglandines selon lequel les groupes benzoyl et p-nitrobenzoyl sont employés comme groupes protecteurs d'hydroxyl. L'invention porte également sur une composition pharmaceutique contenant les dérivés de prostaglandines.
PCT/IN2011/000484 2010-07-23 2011-07-21 Préparation de dérivés de prostaglandines Ceased WO2012011128A1 (fr)

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IN2109CH2010 2010-07-23
IN2109/CHE/2010 2010-07-23

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WO2012011128A1 true WO2012011128A1 (fr) 2012-01-26

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CN108084073A (zh) * 2017-12-05 2018-05-29 重庆药友制药有限责任公司 一种纯化贝美前列素的方法
CN109232494A (zh) * 2018-10-29 2019-01-18 常州博海威医药科技股份有限公司 一种比马前列腺素关键中间体的制备方法
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JPWO2020195437A1 (fr) * 2019-03-27 2020-10-01
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WO2022138586A1 (fr) 2020-12-23 2022-06-30 協和ファーマケミカル株式会社 Procédé de séparation d'isomère géométrique
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US10456293B2 (en) 2012-10-26 2019-10-29 Forsight Vision5, Inc. Ophthalmic system for sustained release of drug to eye
CN103288698A (zh) * 2013-05-07 2013-09-11 北京洛斯顿精细化工有限公司 一种合成前列素类似物的新方法
US11224602B2 (en) 2015-04-13 2022-01-18 Forsight Vision5, Inc. Ocular insert composition of a semi-crystalline or crystalline pharmaceutically active agent
CN108084073A (zh) * 2017-12-05 2018-05-29 重庆药友制药有限责任公司 一种纯化贝美前列素的方法
CN108084073B (zh) * 2017-12-05 2019-10-29 重庆药友制药有限责任公司 一种纯化贝美前列素的方法
CN109232494A (zh) * 2018-10-29 2019-01-18 常州博海威医药科技股份有限公司 一种比马前列腺素关键中间体的制备方法
KR20210143744A (ko) 2019-03-27 2021-11-29 교와 파마 케미칼 가부시키가이샤 프로스타글란딘의 제조 방법
CN113557227A (zh) * 2019-03-27 2021-10-26 协和医药化工股份有限公司 前列腺素的制造方法
WO2020195437A1 (fr) 2019-03-27 2020-10-01 協和ファーマケミカル株式会社 Procédé de production de prostaglandine
JPWO2020195437A1 (fr) * 2019-03-27 2020-10-01
EP3950672A4 (fr) * 2019-03-27 2023-01-11 Kyowa Pharma Chemical Co., Ltd. Procédé de production de prostaglandine
TWI838487B (zh) * 2019-03-27 2024-04-11 日商協和醫藥化工股份有限公司 前列腺素之製造方法
WO2022138586A1 (fr) 2020-12-23 2022-06-30 協和ファーマケミカル株式会社 Procédé de séparation d'isomère géométrique
CN116583500A (zh) * 2020-12-23 2023-08-11 协和医药化工股份有限公司 几何异构体的分离方法
EP4261206A4 (fr) * 2020-12-23 2024-10-30 Kyowa Pharma Chemical Co., Ltd. Procédé de séparation d'isomère géométrique
CN115677549A (zh) * 2022-10-27 2023-02-03 神隆医药（常熟）有限公司 一种贝美前列素手性异构体的制备方法

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